Journal
CHEMMEDCHEM
Volume 14, Issue 21, Pages 1863-1872Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900508
Keywords
brain penetration; drug resistance; genetic barriers; HIV-1 protease inhibitors; structure-based design
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Funding
- National Institutes of Health [AI150466, AI150461]
- Georgia State University Molecular Basis of Disease Fellowship
- Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health [R01AI121315]
- Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu-Kagakusho)
- Japan Agency for Medical Research and Development (AMED) [JP15fk0410001, JP18fk0410001]
- National Center for Global Health and Medicine Research Institute
- US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]
- Ministry of Health, Welfare, and Labor of Japan
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We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2' ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC50 value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme K-i but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIVDRV (R)(P20) and HIVDRV (R)(P30) viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions.
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